title: Population pharmacokinetic-pharmacodynamic modeling of haloperidol in patients with schizophrenia using positive and negative syndrome rating scale.
abstract: The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PKPD) model that quantifies the efficacy of haloperidol, accounting for the placebo effect, the variability in exposure-response, and the dropouts. Subsequently, the developed model was utilized to characterize an effective dosing strategy for using haloperidol as a comparator drug in future antipsychotic drug trials. The time course of plasma haloperidol concentrations from 122 subjects and the Positive and Negative Syndrome Scale (PANSS) scores from 473 subjects were used in this analysis. A nonlinear mixed-effects modeling approach was utilized to describe the time course of PK and PANSS scores. Bootstrapping and simulation-based methods were used for the model evaluation. A 2-compartment model adequately described the haloperidol PK profiles. The Weibull and Emax models were able to describe the time course of the placebo and the drug effects, respectively. An exponential model was used to account for dropouts. Joint modeling of the PKPD model with dropout model indicated that the probability of patients dropping out is associated with the observed high PANSS score. The model evaluation results confirmed that the precision and accuracy of parameter estimates are acceptable. Based on the PKPD analysis, the recommended oral dose of haloperidol to achieve a 30% reduction in PANSS score from baseline is 5.6 mg/d, and the corresponding steady-state effective plasma haloperidol exposure is 2.7 ng/mL. In conclusion, the developed model describes the time course of PANSS scores adequately, and a recommendation of haloperidol dose was derived for future antipsychotic drug trials.
authors.affiliation: From the *Division of Pharmacokinetics, Toxicology and Targeting, University Centre for Pharmacy, University of Groningen, the Netherlands; †Advanced PKPD Modeling and Simulation, Janssen Research & Development, Beerse, Belgium; ‡Clinical Pharmacology, Pfizer Global Research and Development, Groton, CT; §Clinical PK-PD, Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck Research Labs, Merck Sharp & Dohme, Oss, the Netherlands; ∥Department of Psychiatry, Ludwig Maximilians University, Munich, Germany; and ¶Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, the Netherlands.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Pilla Reddy
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kozielska
authors.forename: Martin
authors.initials: M
authors.lastname: Johnson
authors.forename: Nyashadzaishe
authors.initials: N
authors.lastname: Mafirakureva
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Rik
authors.initials: R
authors.lastname: de Greef
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: Geny M M
authors.initials: GM
authors.lastname: Groothuis
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Proost
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006220:Haloperidol / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D017711:Nonlinear Dynamics; D010352:Patient Dropouts; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000188:drug therapy*; D013997:Time Factors; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D006220:Haloperidol